Combination therapy
A new method of treating liver cancer has been developed
Skoltech blog, Naked Science
Researchers at Skoltech and the Massachusetts Institute of Technology (MIT) have announced a new method of combined therapy for liver cancer. They showed that activation of apoptosis – programmed cell death – in combination with chemotherapy effectively inhibit the growth of hepatocellular carcinoma in a mouse model.
The researchers used technologies for regulating protein expression (RNA interference, Professor Zatsepin's group, Skoltech) and targeted delivery of miRNA using lipid nanoparticles (Professor Anderson's group, MIT). The work was published in an article in the journal Molecular Therapy (Leboeuf et al., Downregulation of the Arg/N-degron Pathway Sensitizes Cancer Cells to Chemotherapy In Vivo).
The incidence of liver tumors in the world has tripled since 1980, as a result of which these malignant neoplasms have reached the fourth place among other cancers. There are no effective approaches for the treatment of the late stages of this aggressive disease.
Only recently, the multikinase inhibitor regorafenib and two cell cycle checkpoint inhibitors have been approved for patients who have sorafenib (a targeted antitumor agent) it was ineffective, but even these drugs increase the overall life expectancy by only three months, which indicates a high need for new methods of treatment.
"Our approach is to turn off the mechanism that prevents cell death in liver cells," comments Dominique Lebof, a graduate student at Skoltech and the first author of the article. "As soon as the mechanism is turned off, the cells become more sensitive to chemotherapy, which should kill tumor cells and prevent division. Despite the fact that our miRNA penetrates the entire liver, it is the tumor cells that are most sensitive to chemotherapy, as they divide quickly. And that's why they die, and normal cells survive."
The left shows the normal way of regulation of the degron (the part of the protein molecule that regulates the rate of its destruction). On the right is the path leading to negative regulation of degron / ©molecular-therapy.
These impressive data are the result of a long collaboration of scientific groups led by Professors Konstantin Pyatkov, Timofey Zatsepin and Dan Anderson. The research was funded under the NGP program, and experiments were conducted in the laboratories of both Skoltech and MIT, which made it possible not only to use the potential of both teams, but also allowed employees to exchange experience and students to acquire new knowledge.
"This study was born from the hypothesis of Professor Pyatkov, which was formulated immediately after the creation of a joint scientific group at Skoltech. Our article is the result of a combination of Konstantin's knowledge about the mechanisms of protein degradation, mine in the use of RNA interference, and Daniel Anderson's in the delivery methods of therapeutic nucleic acids. First, Dominique confirmed the main property of any antitumor drug being developed: selective action on tumor cells, but not on normal cells.
Together with the laboratory of Dan Anderson at MIT, we were then able to show the effectiveness of the proposed approach on animals. We are confident that miRNAs in combination with other drugs can help in the treatment of many diseases that have been difficult to treat up to now," said Professor Timofey Zatsepin.
"The combined approach proposed in this study is potentially applicable to the treatment of all types of malignant tumors, since the proteins that we suppress are present in all types of cells. Our solution is universal and simple, and we hope that it can eventually help many patients," said the head of the study, Professor Konstantin Pyatkov.
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